US3694447A - Complexes of phosphanilic acid and 9-amino-3-nitroacridine - Google Patents
Complexes of phosphanilic acid and 9-amino-3-nitroacridine Download PDFInfo
- Publication number
- US3694447A US3694447A US18312A US3694447DA US3694447A US 3694447 A US3694447 A US 3694447A US 18312 A US18312 A US 18312A US 3694447D A US3694447D A US 3694447DA US 3694447 A US3694447 A US 3694447A
- Authority
- US
- United States
- Prior art keywords
- amino
- nitroacridine
- complexes
- activity
- pseudomonas
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- OAOBMEMWHJWPNA-UHFFFAOYSA-N (4-aminophenyl)phosphonic acid Chemical compound NC1=CC=C(P(O)(O)=O)C=C1 OAOBMEMWHJWPNA-UHFFFAOYSA-N 0.000 title claims abstract description 25
- RFGXJQLQGRJKMD-UHFFFAOYSA-N 3-nitroacridin-9-amine Chemical compound [O-][N+](=O)C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 RFGXJQLQGRJKMD-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000002253 acid Substances 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- XJGFWWJLMVZSIG-UHFFFAOYSA-N 9-aminoacridine Chemical compound C1=CC=C2C(N)=C(C=CC=C3)C3=NC2=C1 XJGFWWJLMVZSIG-UHFFFAOYSA-N 0.000 abstract description 3
- 229960001441 aminoacridine Drugs 0.000 abstract description 3
- 230000000843 anti-fungal effect Effects 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 241000589516 Pseudomonas Species 0.000 description 10
- 241000589774 Pseudomonas sp. Species 0.000 description 10
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 10
- 229960001907 nitrofurazone Drugs 0.000 description 10
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 9
- 239000002674 ointment Substances 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 239000000344 soap Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- -1 acridine compound Chemical class 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000008267 milk Substances 0.000 description 5
- 210000004080 milk Anatomy 0.000 description 5
- 235000013336 milk Nutrition 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 4
- 229930182566 Gentamicin Natural products 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 244000309466 calf Species 0.000 description 4
- 229960002518 gentamicin Drugs 0.000 description 4
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 4
- 229960004068 hexachlorophene Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 3
- 229940100615 topical ointment Drugs 0.000 description 3
- GHCKERHPOQWERJ-UHFFFAOYSA-N 3-aminoacridine Chemical compound C1=CC=CC2=NC3=CC(N)=CC=C3C=C21 GHCKERHPOQWERJ-UHFFFAOYSA-N 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- TYMRLRRVMHJFTF-UHFFFAOYSA-N Mafenide Chemical compound NCC1=CC=C(S(N)(=O)=O)C=C1 TYMRLRRVMHJFTF-UHFFFAOYSA-N 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 241000334216 Proteus sp. Species 0.000 description 2
- 208000032536 Pseudomonas Infections Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229960003640 mafenide Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 229960003600 silver sulfadiazine Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000003860 topical agent Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- SIACJRVYIPXFKS-UHFFFAOYSA-N (4-sulfamoylphenyl)methylazanium;chloride Chemical compound Cl.NCC1=CC=C(S(N)(=O)=O)C=C1 SIACJRVYIPXFKS-UHFFFAOYSA-N 0.000 description 1
- DEEULBIVHZVMHX-UHFFFAOYSA-N 1-nitroacridine Chemical compound C1=CC=C2C=C3C([N+](=O)[O-])=CC=CC3=NC2=C1 DEEULBIVHZVMHX-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- QFSMBYCXODQZJA-UHFFFAOYSA-N 2-nitroacridin-9-amine Chemical compound C1=C([N+]([O-])=O)C=C2C(N)=C(C=CC=C3)C3=NC2=C1 QFSMBYCXODQZJA-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 241000577218 Phenes Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 150000001251 acridines Chemical class 0.000 description 1
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 201000010251 cutis laxa Diseases 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 210000004915 pus Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
- C07D219/10—Nitrogen atoms attached in position 9
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3834—Aromatic acids (P-C aromatic linkage)
Definitions
- This invention in its broadest aspect, comprises complexes of phosphanilicacid and an antibacterial acridine.
- the invention in a more limited aspect, comprises complexes of phosphanilic acid and an aminoacridine, preferably a 9-amino, 3-arnino, or 6-aminoacridine,
- the invention in a still more limited aspect, comprises l:'l and 2:1 complexes of phosphanilic acid (I) and a 9-amino,3-amino, or 6-aminoacridine.(ll), said acridine being additionally substituted with one or more amino, methyl, ethyl, chloro, bromo, nitro, methoxy, ethoxy, cyano, phenyl, orrelated groups and also havingantibacterial activity.
- each R is NH, orH, at least one of such groups being N11 and each R is' hydrogen, amino, methyl, ethyl, methoxy, ethoxy, chloro, bromo,nitro, cyano, or phenyl.
- the invention in its preferred aspect, comprises the 1:1 and 2:1 complexes of phosphanilic acid and 9- ;amino-B-nitroacridine (Ill).
- hexamethyl phosphoramide may be used. Choice of appropriate solvents is wellwithin the skill of theart.
- test compound isincorporated in agar attwo-fold levels from 200 Lg/ml downward, and the test organisms inoculated onto-the hardened agar surface. Activity is measured as the lowest concentra tion which prevents growth of the test organism.
- the 1:1 complex was further tested for activity against a total of 77 strains of Gram-positive and negative bacteria, including 40 strains of Pseudomonas, an organism found difficult to cope with clinically, plus 8 strains of yeast and fungi. Of this spectrum, almost all were recent clinical isolates.
- An antimicrobial agent to be effective in vivo, must be capable of retaining its activity in the presence of a variety of substances, including whole blood, serum, sebum, pus, and other body fluids.
- a topical antimicrobial intended for human use must also remain effective when applied to skin which retains traces of soap.
- substantivity of a compound, or its ability to be retained by the cells of the skin is a valuable characteristic for topical agents. Hexachlorophenes ability to do so is well known and serves as one of its major attractions, offsetting its limited spectrum of activity.
- Experiments were carried out to assess the in vitro substantivity of SK&F 36387J, hexachlorophene and nitrofurazone using an in vitro method utilizing skin discs. In this system, standardized calf skin discs are immersed in solutions of drug for 30 minutes, then vigorously washed in running water for extended period of time. Washed discs are then placed on agar surfaces inoculated with Staphylococcus aureus and Pseudomonas sp.
- Antimicrobial agents can be shown to exert either of two types of efi'ects on bacterial cells: a truly lethal, irreversible, action termed bactericidal, or a reversible action in which the organism, rendered free of the agent, can again multiply, in which case it is termed bacteriostatic.
- bactericidal a truly lethal, irreversible, action termed bactericidal
- bacteriostatic a truly lethal, irreversible, action termed bactericidal
- bacteriostatic a truly lethal, irreversible, action termed bactericidal
- a reversible action in which the organism, rendered free of the agent can again multiply, in which case it is termed bacteriostatic.
- bacteriostatic To determine whether the activity of SK&F 36387-J is bactericidal or bacteriostatic, the following experiment was carried out. Two-fold dilutions of SK&F 36387-J in broth were inocul
- Silver sulfadiazine was consistently effective at levels approximately 2X higher than SK&F 36387-J and gentamicin. Mafenide, however, displayed activity only at test levels 8X to 16X higher than the other compounds.
- An additional experiment was conducted to determine the ability of SK&F 36387-J to prolong the lifetimes of burned mice infected with Pseudomonas. Male, albino, Charles River mice (14-18 grams) were burned by immersing the tails of etherized animals in water at 70C for 5 seconds. Inoculation with Pseudomonas aeruginosa (ATCC No. 19660, NIH No. 180) was carried out 2 hours later by dipping the burned tails in an 18 hour broth culture of the organism.
- mice were then encased in soft latex tubing three-sixteenths inch bore, one-sixteenth inch wall) which was stapled to the loose skin at the base of the tail with Michel wound clips.
- a single applica- 60 tion of the test ointment (approximately 1.0 ml) was injected into the sheath enclosing the tail and the end of the sheath closed with a size 00 cork to avoid ointment loss.
- Mice were observed daily for deaths during the entire 12 day duration of the test.
- Heart blood and the 5 kidneys of mice which died were cultured for viable organisms; in all cases, Pseudomonas was recovered, indicating a Pseudomonas septicemia. Results are shown in Table l 1.
- SK&F 36387-1 in a 0.2 percent ointment, provided excellent protection against the. Pseudomonas aeruginosa infection produced in burned mice.
- the protection provided by a-single application waslong lasting, with 90 percent of the animals still protected on the l2th'day after treatment.
- 'Gentamicin ointment provided initial protection equal to that ,of SK&F 36387-4, ,but its protective effect decreased with time.
- Commercial nitrofurazone ointment (0.2 percent) was protective for the firstfew days of the test only; by the tests end, 70 percent of the treated animals had died. Untreated, infected animals quickly succumbed to their Pseudomonas infections! (77 percent died by day 3); the burn control animals (no infection) survived the test with only 4/40 deaths.
- The-complexes of the present invention are intended? to be used topically.- They are forrnulatedfor such use 5 by combining-them with appropriate topically acceptable carriers or vehicles and other materials to form antiseptic solutions, soaps, shampoos, lotions, ointment's, creams, toothpaste, powders, mouthwashes, etc.
- suitable topically acceptable carriers or vehicles and other materials to form antiseptic solutions, soaps, shampoos, lotions, ointment's, creams, toothpaste, powders, mouthwashes, etc.
- a solution should contain about 0.0l-l0 percent of the complex.
- a topical ointment should contain about 0.025-0.5 percent of the complex.
- EXAMPLE 2 2:1 Complex of Phosphanilic Acid and 3-Nitro-9- aminoacridine To a warm solution of 42 g. (0.176 m.) of 3-nitro-9- aminoacridine in 450 ml. of dimethyl sulfoxide was added a hot solution of 68.5 g. (0.39 m. 'ofphosflanilsolution was stirred vigorously while 5,600 ml. of hot water was rapidly added. The reaction mixture was cooled to about 10C. and the product separated by filtration, washed with water and dried in vacuo at 100C.
- Antiseptic solution 0.05% w/v solution of the 1: 1 complex of phosphanilic acid and 9-amino-3-nitroacridine in 50 percent glycerin. Pure glycerin may also be used as solvent.
- Span 60 (Sorbitan monostearate) 2.100
- a complex according to claim 1 consisting of 9- aminQS-nitroacridine and 2 equivalents of phosphaniic acid.
- a complex according to claim 1 consisting of 9- amino-3-nitroacridine and 1 equivalent of phosphanilic acid.
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Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1831270A | 1970-03-10 | 1970-03-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3694447A true US3694447A (en) | 1972-09-26 |
Family
ID=21787296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US18312A Expired - Lifetime US3694447A (en) | 1970-03-10 | 1970-03-10 | Complexes of phosphanilic acid and 9-amino-3-nitroacridine |
Country Status (14)
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3873547A (en) * | 1973-05-02 | 1975-03-25 | Merck & Co Inc | The salt of 3-nitro-9-aminoacridine and -(cis)-1,2-epoxypropylphosphonic acid |
| DE3016110A1 (de) * | 1979-04-26 | 1980-11-06 | Bristol Myers Co | Antibakterielle verbindungen, verfahren zu ihrer herstellung und daraus hergestellte mittel |
| US4666896A (en) * | 1979-04-26 | 1987-05-19 | Bristol-Myers Company | Chlorhexidine salts and compositions of same |
| US5200402A (en) * | 1991-10-24 | 1993-04-06 | U.S. Army Medical Research & Development Command | Anti microbial mafenide-phosphanilate compound, pharmaceutical compositions and method of use therefor |
| WO2001060351A2 (en) | 2000-02-18 | 2001-08-23 | New York Medical College | Nitroacridine/tumor inhibitor compositions |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4177199A (en) * | 1978-12-11 | 1979-12-04 | Bristol-Myers Company | Silver salts of phosphanilic acid |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2092131A (en) * | 1937-09-07 | S-of amino ackibines | ||
| US2245539A (en) * | 1938-07-29 | 1941-06-10 | Hoffmann La Roche | Sulphanilamide phosphoric acid derivative and process for the manufacture thereof |
| US2605280A (en) * | 1948-01-13 | 1952-07-29 | Irving M Klotz | p-aminobenzenephosphonous acid |
| US3122553A (en) * | 1959-08-20 | 1964-02-25 | Bansen Inc | 4-alkyl resorcinolates of aminoacridines |
| US3346579A (en) * | 1966-04-25 | 1967-10-10 | Squibb & Sons Inc | Iodine chloride complexes of quinoline and acridine compounds |
| US3442938A (en) * | 1967-01-31 | 1969-05-06 | Merck & Co Inc | Prosphanilic acid derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1542331A (fr) * | 1966-11-07 | 1968-10-11 | Stauffer Chemical Co | Nouveaux composés organophosphorés azotés et leurs applications comme pesticides |
-
1970
- 1970-03-10 US US18312A patent/US3694447A/en not_active Expired - Lifetime
-
1971
- 1971-02-04 CA CA104,464A patent/CA973186A/en not_active Expired
- 1971-02-04 IL IL36136A patent/IL36136A/xx unknown
- 1971-02-06 IN IN130204A patent/IN130204B/en unknown
- 1971-02-09 ZA ZA710794A patent/ZA71794B/xx unknown
- 1971-02-15 BE BE762951A patent/BE762951A/xx unknown
- 1971-02-15 DK DK67071AA patent/DK126503B/da unknown
- 1971-02-17 FR FR7105340A patent/FR2085688B1/fr not_active Expired
- 1971-02-25 IT IT21038/71A patent/IT1017507B/it active
- 1971-03-01 NL NL7102690A patent/NL7102690A/xx unknown
- 1971-03-09 FI FI710685A patent/FI49963C/fi active
- 1971-03-10 CH CH350571A patent/CH554902A/xx not_active IP Right Cessation
- 1971-03-10 DE DE19712111521 patent/DE2111521A1/de active Pending
- 1971-04-19 GB GB1290640D patent/GB1290640A/en not_active Expired
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2092131A (en) * | 1937-09-07 | S-of amino ackibines | ||
| US2245539A (en) * | 1938-07-29 | 1941-06-10 | Hoffmann La Roche | Sulphanilamide phosphoric acid derivative and process for the manufacture thereof |
| US2605280A (en) * | 1948-01-13 | 1952-07-29 | Irving M Klotz | p-aminobenzenephosphonous acid |
| US3122553A (en) * | 1959-08-20 | 1964-02-25 | Bansen Inc | 4-alkyl resorcinolates of aminoacridines |
| US3346579A (en) * | 1966-04-25 | 1967-10-10 | Squibb & Sons Inc | Iodine chloride complexes of quinoline and acridine compounds |
| US3442938A (en) * | 1967-01-31 | 1969-05-06 | Merck & Co Inc | Prosphanilic acid derivatives |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3873547A (en) * | 1973-05-02 | 1975-03-25 | Merck & Co Inc | The salt of 3-nitro-9-aminoacridine and -(cis)-1,2-epoxypropylphosphonic acid |
| DE3016110A1 (de) * | 1979-04-26 | 1980-11-06 | Bristol Myers Co | Antibakterielle verbindungen, verfahren zu ihrer herstellung und daraus hergestellte mittel |
| US4666896A (en) * | 1979-04-26 | 1987-05-19 | Bristol-Myers Company | Chlorhexidine salts and compositions of same |
| US5200402A (en) * | 1991-10-24 | 1993-04-06 | U.S. Army Medical Research & Development Command | Anti microbial mafenide-phosphanilate compound, pharmaceutical compositions and method of use therefor |
| WO1993007880A1 (en) * | 1991-10-24 | 1993-04-29 | The United States Of America, As Represented By The Secretary Of The Army | Anti-microbial mafenide-phosphanilate compound, pharmaceutical compositions and method of use therefor |
| WO2001060351A2 (en) | 2000-02-18 | 2001-08-23 | New York Medical College | Nitroacridine/tumor inhibitor compositions |
| US20020037831A1 (en) * | 2000-02-18 | 2002-03-28 | Raj Tiwari | 1-Nitroacridine/tumor inhibitor compositions |
| US7622478B2 (en) | 2000-02-18 | 2009-11-24 | Raj Tiwari | 1-nitroacridine/tumor inhibitor compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| NL7102690A (enrdf_load_stackoverflow) | 1971-09-14 |
| CA973186A (en) | 1975-08-19 |
| IL36136A0 (en) | 1971-04-28 |
| FI49963C (fi) | 1975-11-10 |
| GB1290640A (enrdf_load_stackoverflow) | 1972-09-27 |
| DE2111521A1 (de) | 1971-09-30 |
| IN130204B (enrdf_load_stackoverflow) | 1975-09-20 |
| BE762951A (fr) | 1971-08-16 |
| ZA71794B (en) | 1971-10-27 |
| FR2085688B1 (enrdf_load_stackoverflow) | 1974-08-23 |
| FR2085688A1 (enrdf_load_stackoverflow) | 1971-12-31 |
| IT1017507B (it) | 1977-08-10 |
| FI49963B (enrdf_load_stackoverflow) | 1975-07-31 |
| DK126503B (da) | 1973-07-23 |
| IL36136A (en) | 1974-06-30 |
| CH554902A (de) | 1974-10-15 |
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